DESCRIPTION: (Applicant's Description) Epidemiological studies, as well as studies in laboratory animals, suggest that polyphenols, present in fruits, vegetables and beverages, have protective effects in a variety of cancers. A rapidly growing number of biochemical studies show a vast array of plausible mechanisms for these effects. However, it is not clear to what extent and in which form the dietary polyphenols are absorbed in the human intestine and thus can gain access to proposed cellular sites of action. As clinical and animal studies of the bioavailability of the polyphenols in general have been unsuccessful, we are using an intermediary preclinical approach, using the Caco-2 cell line as model of human intestinal absorption as well as metabolism. The proposed study is focusing on the polyphenol resveratrol, a phytoalexin in grapes and red wine. Our working hypothesis is that the Caco-2 cell model is highly predictive of both absorption and metabolism of resveratrol in humans in vivo. In Aim 1 we will in first hand determine the absorption, i.e. apical to basolateral transport across the Caco-2 cell monolayer, of resveratrol, using a molecularly specific HPLC assay. This will also yield the metabolic fate of resveratrol, including potential oxidation as well as conjugation products, identified by HPLC/MS and other spectroscopic methods. Dose-dependency in transport and metabolism will be of particular concern. Corresponding studies of ex sorption, i.e. basolateral to apical transport, will be done in order to determine the possible directional transport of resveratrol and its metabolites mediated by efflux pumps, such as P-glycoprotein and the MRPs. In addition, we will identify the drug metabolizing enzymes involved in resveratrol biotransformation. In Aim 2 we will in first hand determine the oral bioavailability of resveratrol. This will require the administration of both an oral (25 mg) and an intravenous (1 mg) dose. Fifty microCi of (14C)-labeled resveratrol will be administered with each dose to make it possible to determine recoveries and the complete metabolic fate of resveratrol. This will also make it possible to assess fecal elimination, the major route of elimination of polyphenols. From these data we will determine the pharmacokinetic parameters for resveratrol, including clearances (total, renal, metabolic, fecal), elimination half -life and volume of distribution. Together Aims 1 and 2 will let us determine the usefulness of the Caco-2 cells as a preclinical model.